Depression and Long-term Codeine Use
Abstract & Commentary
Synopsis: Some patients who use codeine on a long-term basis may be attempting to improve psychiatric symptoms such as mood disturbances. This report attempts to examine the relationship of long-term codeine use to depressive symptoms.
Source: Romach MK, et al. Long-term codeine use is associated with depressive symptoms. J Clin Psychopharmacol 1999;19:373-376.
Epidemiologic reports have shown that the use of opioids (of which 60% to 75% is codeine) in Canada has slowly increased from 1978 to 1989. The current study, performed by researchers from the University of Toronto, was designed to provide descriptive data on the widespread use of codeine and to elucidate information related to the cause of the increased consumption.
The authors hypothesized that many patients who seek long-term treatment with codeine may in fact be attempting to ameliorate problems other than pain, such as improvements in mood. In the current study, subjects who had been using codeine at least three days per week for a minimum of six months were recruited via newspaper advertisements and subsequent telephone screening. Subjects were excluded if they were under 16 years of age or if they were receiving codeine for pain related to malignancy. Eligible subjects were sent a 212 item, questionnaire consisting of the following domains: demographics, patterns of use, past and current use of other psychotropics, health status questions including the Symptom Checklist-90 (SCL-90), and family history of substance use and mental health problems. Of the initial questionnaires sent by mail, 70% responded and a total of 339 subjects met the study criteria and were included in the analysis. Among the respondents, codeine dependence/abuse (according to DSM-IV criteria) was present in 41%. The SCL-90 scores were modestly elevated in comparison with published norms, with the most marked elevations present on the Depression subscale. On the Inventory of Drug Taking Situations, which provides a profile of situations leading to drug use, the most marked elevations were present on the Physical Discomfort and Unpleasant Emotions subscales. The authors suggest that these data are suggestive of a strong relationship between depression and long-term codeine use. It is unclear from the current study whether the patients are using codeine to "self-medicate" for psychiatric problems or that patients who have chronic pain are also likely to develop depression.
Comment by Michael F. Barber, PharmD
Patients with depression frequently present to physicians complaining of multiple somatic symptoms, such as headaches, back pain, etc. Logically, patients who seek long-term treatment with opioids such as codeine may, in fact, be seeking an improvement in their mood rather than, or in addition to, relief from physical pain. Thus, patients who may be dependent on opioids might also be suffering from depression. As a result, these patients with untreated depression are likely to continue to seek opioids even if they are being treated in a substance abuse program. Therefore, patients with opioid dependence/abuse should be screened for depression and given antidepressants and/or psychotherapy as indicated in addition to referral for substance abuse treatment.
It should be noted that there is a clinically important drug interaction between codeine and some antidepressants. Since codeine is O-demethylated to its active form (morphine), this cytochrome P450 2D6 (CYP2D6) enzyme-mediated reaction can be inhibited by certain medications. Almost all of the selective serotonin reuptake inhibitors can inhibit CYP2D6. Paroxetine (Paxil) is the most potent inhibitor, while fluoxetine (Prozac) and fluvoxamine (Luvox) can cause a moderate level of inhibition as well. At doses below 150 mg/day, sertraline (Zoloft) causes only slight inhibition of CYP2D6, whereas higher doses may cause clinically important drug interactions. Citalopram (Celexa) does not inhibit CYP2D6 to any appreciable extent. The inhibition of CYP2D6 by antidepressants, as well as other medications, decreases the analgesic effects of codeine. Essentially, codeine is not converted to morphine. As such, patients receiving CYP2D6 inhibitors concomitantly with codeine preparations may request increases in narcotic dosing due to lack of pain relief. This is often interpreted as drug-seeking behavior and subsequent decreases in the amount of codeine prescribed, leading to a worsening of the patient's condition. This dilemma can be corrected by switching antidepressants or switching opioids. Although the coadministration of CYP2D6 inhibitors will inhibit the conversion of oxycodone (present in compounds such as Tylox, Percocet, Percodan) to oxymorphone, the analgesic effect is retained since oxycodone itself is active. Thus far, codeine is the only opioid which has been reported to require biotransformation to an active analgesic compound for analgesic activity
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